Project Abstract Primary liver cancer, and specifically hepatocellular carcinoma (HCC), is the third most common cause of cancer death worldwide. In patients with intermediate-stage or unresectable HCC, transarterial chemoembolization (TACE) is the most widely used therapy. The success of TACE critically depends on the accurate and complete targeting of the tumor. While x-ray image guidance is routinely used to qualitatively visualize the drug delivery, it currently does not enable quantitative guidance and assessment to determine appropriate delivery endpoints. Therefore, TACE endpoints are highly variable across operators and patients, with poor ability to predict tumor response and patient outcome. To accurately monitor drug accumulation in the tumor, real-time quantification of radiopaque iodine (mixed with the drug prior to delivery) is needed with every x-ray image, a concept we entitle single-shot quantitative imaging (SSQI). SSQI is not currently possible due to several challenges with x-ray imaging, including scatter, multiple overlaying materials, and patient and system motion. We therefore propose robust SSQI enabled by the combination of a primary modulator and a dual-layer detector to quantify iodine areal density in real time. The primary modulator provides scatter correction, while the dual-layer detector provides material-specific images with each exposure. The resulting SSQI system provides iodine quantification and dose-efficient grayscale images that are robust against motion. A key strength of the proposed solution is its simplicity in hardware and software ? it is compatible with existing system designs, without introducing new complexities or challenges. Our specific aims include: 1) Build a prototype SSQI system. We will design and construct a primary modulator with optimized material, pitch, and thickness, as well as a dual-layer detector with optimized scintillator thicknesses and filter for quantifying iodine in abdominal imaging. We will also develop a real-time image processing pipeline to convert the modulated dual-layer images into quantitative images. 2) Assess the quantitative imaging accuracy of prototype SSQI system. We will evaluate the material quantification accuracy for iodine tasks representative of TACE using phantoms of various sizes with known amounts of iodine, bone, and other tissue-equivalent materials. We hypothesize that SSQI can achieve accurate iodine quantification and grayscale accuracy, while being dose efficient. The proposed studies will establish a new x-ray imaging paradigm that brings quantitation to every image by simultaneously overcoming several current limitations of x-ray imaging while retaining traditional advantages such as high spatial and temporal resolution and large-area imaging. The simplicity and broad applicability of SSQI to x-ray systems has the potential for widespread adoption as a platform for quantitative imaging.